Overexpression of Aurora-A kinase promotes tumor cell proliferation and inhibits apoptosis in esophageal squamous cell carcinoma cell line

Wang, Xiao Xia; Liu, Rong; Jin, Shun Qian; Fan, Fei; Zhan, Qiang

doi:10.1038/sj.cr.7310046

Cited by 81 publications

(58 citation statements)

References 19 publications

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“…For example, overexpression of Aurora-A has been reported to induce cellular transformation in NIH3T3 fibroblasts (Zhou et al, 1998). Increased expression of Aurora-A has also been found to promote cell proliferation in esophageal cancer cells (Wang et al, 2006). Our present results indicate that overexpression of Aurora-A markedly interferes with RASSF1A-induced growth suppression.…”

Section: Discussionsupporting

confidence: 61%

Mitotic kinase Aurora-A phosphorylates RASSF1A and modulates RASSF1A-mediated microtubule interaction and M-phase cell cycle regulation

et al. 2007

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RASSF1A (RAS-association domain family 1, isoform A) is a newer tumor suppressor that binds to and stabilizes microtubules as well as induces M-phase cell cycle arrest. Several other proteins that interact with and stabilize microtubules also undergo mitotic phase phosphorylation to regulate microtubule dynamics and M-phase cell cycle progression. Currently, however, there is a paucity of information regarding the phosphorylation status of RASS-F1A and its regulation during mitosis. In this study, for the first time, we demonstrate that Aurora-A is a RASSF1A kinase and, to the best of our knowledge, this is also the first study reporting the identification of a kinase for RASSF1A. We show that the mitotic kinase Aurora-A directly interacts with and phosphorylates RASSF1 and that RASSF1A is phosphorylated by Aurora-A during mitosis. These findings therefore link an important oncogenic mitotic kinase to regulate RASSF1A tumor suppressor. Aurora-A appears to phosphorylate RASSF1A at Threonine202 and/or Serine203 that reside within the known microtubule-binding domain of RASSF1A. Substitutions of these residues with glutamic acid at both positions, mimicking constitutive phosphorylation of RASSF1A, disrupt RASSF1A interactions with microtubules and abolish its ability to induce M-phase cell cycle arrest. Our results further demonstrate that Aurora-A overexpression also interferes with RASSF1A-mediated growth suppression. In view of our results, we propose that Aurora-A-mediated phosphorylation of RASSF1A is a novel mechanism that regulates the ability of this tumor suppressor to interact with microtubules and modulate M-phase cell cycle progression.

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Section: Discussionsupporting

confidence: 61%

Mitotic kinase Aurora-A phosphorylates RASSF1A and modulates RASSF1A-mediated microtubule interaction and M-phase cell cycle regulation

et al. 2007

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“…Similar findings have also been reported for other centrosome-associated proteins. For example, overexpression of Aurora-A, which is also involved in the control of centrosome maturation, led to a resistance to apoptosis induced by cisplatin (23). In the present study, we found that overexpression of Nlp in HNSCC cells not only conferred a proliferative advantage but also renders cell more resistant to the growth inhibitory and apoptotic effects of cisplatin.…”

Section: Discussionsupporting

confidence: 56%

Ninein-like protein is overexpressed in head and neck squamous cell carcinoma and contributes to cancer growth and resistance to apoptosis

Zhan¹

2009

Oncol Rep

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Abstract. Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and survival rates are not improving. Better understanding of the molecular mechanisms of this disease becomes critical to develop more effective treatments. Ninein-like protein (Nlp), a recently identified centrosome-associated protein, is a key regulator in centrosome maturation, which contributes to chromosome segregation and cytokinesis. Recent studies have revealed overexpression of Nlp in several types of human tumors and suggested it was a potential oncogenic protein. To investigate the role of Nlp in the development of HNSCC, expression of Nlp in tumor tissues of 76 HNSCC patients were analyzed, and the correlations of Nlp expression with the clinicopathological characteristics were evaluated. Our data showed overexpression of Nlp in tumor tissues compared with their normal counterparts. Moreover, overexpression of Nlp correlated with tumor differentiation and immunohistochemistry analysis of preinvasive dysplasia and squamous cell carcinoma showed that overexpression of Nlp occurred in premalignant lesions. Biological studies with human HNSCC cell lines indicated that overexpression of Nlp promoted cell proliferation and inhibited cisplatin-induced apoptosis. Taken together, these results suggest a novel mechanism that is closely related to malignant phenotype and anti-cancer drugs resistance of HNSCC and support the notion that Nlp overexpression might contribute to the development of HNSCC. IntroductionHead and neck squamous cell carcinoma (HNSCC) accounts for most cancers of the mouth, pharynx and larynx (1). It represents the sixth most frequent cancer worldwide, with an estimated 900,000 cases diagnosed each year (2). Despite advances in surgical and other treatments, HNSCC is still a devastating disease as the survival rates virtually have not changed for the past 30 years (3). While the relatively favorable prognosis for patients diagnosed with early stage HNSCC, >60% of patients apply to hospitals are of advanced stages and the 5-year survival rate for HNSCC patients in stages III and IV (Union International Contre Cancer stages) is <40% (4). Currently, much effort is focused on developing novel strategies for early detection, classification, prevention and treatment of the disease. To fulfill this purpose, a better understanding of the molecular mechanism of HNSCC is underscored.Previously, centrosome amplification have been implicated in the pathogenesis of many types of solid tumors, including HNSCC (5-7). Because centrosomes direct the formation of spindles for the correct separation of chromosomes during mitosis, the presence of more than two centrosomes in a cell can result in lost or fragmented chromosomes after cell division and generation of aneuploidy, which are closely associated with cell transformation and tumorigenesis (7). Ninein-like protein (Nlp), a recently identified centrosomal protein, locates at chromosome 20. During interphase, Nlp is involved in microtubule organization. Two ...

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“…A decrease in cytochrome C release led to inactivation of caspases, thus protecting cells from apoptosis. 33 This antiapoptotic effect was further confirmed in AGS and RIE-1 cells after they were treated with camptothecin. Overexpression of AURKA, therefore, could be a factor that contributes to poor clinical outcome in patients with adenocarcinomas of the stomach and esophagus.…”

Section: Discussionmentioning

confidence: 62%

Frequent overexpression of Aurora Kinase A in upper gastrointestinal adenocarcinomas correlates with potent antiapoptotic functions

Dar¹,

Zaika²,

Piazuelo³

et al. 2008

Cancer

104

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BACKGROUNDUpper gastrointestinal adenocarcinomas are a common cause of cancer‐related deaths. In this study, the authors investigated the prevalence and biological significance of Aurora Kinase A (AURKA) overexpression in upper gastrointestinal adenocarcinomas.METHODSQuantitative real‐time polymerase chain reaction (qRT‐PCR) and immunohistochemical staining on tumor tissue microarrays (TMA) were used to study the expression of AURKA in upper gastrointestinal adenocarcinomas. To investigate the biological and signaling impact of AURKA, the authors used multiple in vitro assays that included 3‐(4, 5‐dimethylthiazol‐2‐yl)‐2, 5‐diphenyltetrazolium bromide (MTT), TUNEL (terminal deoxynucleotidyl transferase–mediated nick‐end labeling), cytochrome C release, flow cytometry, luciferase reporter, and Western blot analysis.RESULTSFrequent overexpression of AURKA transcript in upper gastrointestinal adenocarcinomas was detected compared with normal samples (47%; P = .001). The immunohistochemical analysis of 130 tumors demonstrated moderate‐to‐strong immunostaining of AURKA in >50% of upper gastrointestinal adenocarcinomas. By using camptothecin as a drug‐induced apoptosis in vitro model, the authors demonstrated that the expression of AURKA provided protection against apoptosis to gastrointestinal cancer cells (AGS and RKO) (P = .006) and RIE‐1 primary intestinal epithelial cells (P = .001). The AURKA overexpression mediated an increase in phosphorylation of AKTSer473 with an increase in HDM2 level. The shRNA‐knockdown of AKT in AURKA‐overexpressing cells reversed this effect and showed a significant increase in the p53 protein level, indicating a possible nexus of AURKA/AKT/p53. Indeed, overexpression of AURKA led to a remarkable reduction in the transcription activity of p53, with subsequent reductions in transcript and protein levels of its downstream proapoptotic transcription targets (p21, BAX, NOXA, and PUMA).CONCLUSIONSStudy results indicated that AURKA provides potent antiapoptotic properties to gastrointestinal cells by regulating levels of p53 through the AKT/HDM2 axis. Cancer 2008. ©2008 American Cancer Society.

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Overexpression of Aurora-A kinase promotes tumor cell proliferation and inhibits apoptosis in esophageal squamous cell carcinoma cell line

Cited by 81 publications

References 19 publications

Mitotic kinase Aurora-A phosphorylates RASSF1A and modulates RASSF1A-mediated microtubule interaction and M-phase cell cycle regulation

Mitotic kinase Aurora-A phosphorylates RASSF1A and modulates RASSF1A-mediated microtubule interaction and M-phase cell cycle regulation

Ninein-like protein is overexpressed in head and neck squamous cell carcinoma and contributes to cancer growth and resistance to apoptosis

Frequent overexpression of Aurora Kinase A in upper gastrointestinal adenocarcinomas correlates with potent antiapoptotic functions

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